A Novel Sialyltransferase Inhibitor AL10 Suppresses Invasion and Metastasis of Lung Cancer Cells by Inhibiting Integrin-Mediated Signaling
A Novel Sialyltransferase Inhibitor AL10 Suppresses Invasion and Metastasis of Lung Cancer Cells by Inhibiting Integrin-Mediated Signaling
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DOI：
10.1002/jcp.22068
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发表时间：
2010-05-01
影响因子：
5.6
通讯作者：
Hung, Wen-Chun
中科院分区：
文献类型：
--
作者：
Chiang, Chi-Hsiang;Wang, Chie-Hong;Hung, Wen-Chun
由唾液酸转移酶（ST）催化的异常唾液酸化经常在癌细胞中发现，并且与增加的癌症转移相关。然而，迄今为止开发的ST抑制剂由于其差的细胞渗透性而不适用于临床使用。本研究以石胆酸为先导化合物，合成了一种新型的ST抑制剂AL 10，并对其抗癌作用进行了研究。AL 10是细胞可渗透的，并有效地减弱细胞表面上的总唾液酸化。该抑制剂没有细胞毒性，但抑制α-2，3-ST过表达的A549和CL1.5人肺细胞的粘附、迁移、肌动蛋白聚合和侵袭。AL 10对粘附和迁移的抑制与各种整合素分子的唾液酸化减少和整合素下游信号传导介质粘着斑激酶的活化减弱有关。更重要的是，AL 10在体内显著抑制实验性肺转移，而不影响实验动物的肝和肾功能，如通过血清生化测定所确定的。总之，AL 10是第一个ST抑制剂，其在体内表现出有效的抗转移活性，并可用于临床癌症治疗。J.细胞。223：492-499，2010. (C)2010 Wiley-Liss，Inc.
Aberrant sialylation catalyzed by sialyltransferases (STs) is frequently found in cancer cells and is associated with increased cancer metastasis. However, ST inhibitors developed till now are not applicable for clinical use because of their poor cell permeability. In this study, a novel ST inhibitor AL10 derived from the lead compound lithocholic acid identified in our previous study is synthesized and the anti-cancer effect of this compound is studied. AL10 is cell-permeable and effectively attenuates total sialylation on cell surface. This inhibitor shows no cytotoxicity but inhibits adhesion, migration, actin polymerization and invasion of alpha-2,3-ST-overexpressing A549 and CL1.5 human lung cells. Inhibition of adhesion and migration by AL10 is associated with reduced sialylation of various integrin molecules and attenuated activation of the integrin downstream signaling mediator focal adhesion kinase. More importantly, AL10 significantly suppresses experimental lung metastasis in vivo without affecting liver and kidney function of experimental animals as determined by serum biochemical assays. Taken together, AL10 is the first ST inhibitor, which exhibits potent anti-metastatic activity in vivo and may be useful for clinical cancer treatment. J. Cell. Physiol. 223: 492-499, 2010. (C) 2010 Wiley-Liss, Inc.